Ion channels gated by heat

All animals need to sense temperature to avoid hostile environments and to regulate their internal homeostasis. A particularly obvious example is that animals need to avoid damagingly hot stimuli. The mechanisms by which temp erature is sensed have until recently been mysterious, but in the last coup le of years, we have begun to understand how noxious thermal stimuli are de tected by sensory neurons. Heat has been found to open a nonselective catio n channel in primary sensory neurons, probably by a direct action. Ina sepa rate study, an ion channel gated by capsaicin, the active ingredient of chi li peppers, was cloned from sensory neurons. This channel (vanilloid recept or subtype 1, VR1) is gated by heat in a manner similar to the native heat- activated channel, and our current best guess is that this channel is the m olecular substrate for the detection of painful heat. Both the heat channel and VR1 are modulated in interesting ways. The response of the heat channe l is potentiated by phosphorylation by protein kinase C, whereas VR1 is pot entiated by externally applied protons. Protein kinase C is known to be act ivated by a variety of inflammatory mediators, including bradykinin, wherea s extracellular acidification is characteristically produced by anoxia and inflammation. Both modulatory pathways are likely, therefore, to have impor tant physiological correlates in terms of the enhanced pain (hyperalgesia) produced by tissue damage and inflammation. Future work should focus on est ablishing, in molecular terms, how a single ion channel can detect heat and how the detection threshold can be modulated by hyperalgesic stimuli.